1. Field of the Invention
The role of lipids in cellular growth, differentiation, and activity, is a broad and extensive one. Fatty acids are found in membranes and show a wide variety of hormonal functions. Prostaglandins, thromboxanes, prostacyclin and leukotrienes are illustrative of lipid compounds which have a broad spectrum of physiological properties. These compounds are as a result of oxidation of arachidonic acid and are referred to as eicosanoids.
The eicosanoids are extremely potent, ubiquitous agents with numerous bewildering actions: effect on muscle contraction, platelet aggregation, leukocyte migration and gastric secretion. Lipid compounds which can affect or modulate the arachidonic acid cascade can provide potent physiological agents.
The existence of receptors having specific affinity for the plant-derived phorbol and ingenol ester compounds suggests that the neutrally occurring receptors recognize endogenous ligands which have some structural similarity to phorboids and ingenoids. Prior attempts to isolate and characterize such ligands that interact with these receptors have been unsuccessful, due in part to the existence of phorbol ester binding protein and phorbol diester hydrolase.
It would therefore be of great interest to be able to find either the endogenous ligands or other compounds, differing in minor ways from the endogenous ligands, which would provide for one or more of the biological activities, particularly the physiological activities, of the endogenous ligands.
2. Description of the Prior Art
Dredger and Blumberg, Proc. Natl. Acad. Sci. U.S.A. (1980) 77:567-571; Shoyab and Todaro, Nature (1980) 288:451-455 and Shoyab et al., Carcinogenesis (1981) 2:1273-1276 report the existence of specific high affinity receptors for biologically active phorbol and ingenol esters in a variety of cells and tissues. The difficulties associated with isolating and characterizing ligands that interact with phorboid receptors and induce 12-0-tetradecanoylphorbol-13-acetate ("TPA") like affect in target cells have been reported by Shoyab and Todaro, J. Biol. Chem. (1982) 257:439-445 and Shoyab et al., ibid. (1981) 256:12529-12534.